Treatment of depression with diphenyl prop-2-enylamine derivatives



United States Patent 3,422,203 TREATMENT 0F DEPRESSION WITH DIPHENYL PROP-2-ENYLAMINE DERIVATIVES Roy Frederick Maisey, Macclesfield, England, assignor to Geistlich, Ed. Sohne AG fur Chemische Indnstrie, a Swiss body corporate No Drawing. Filed Feb. 13, 1967, Ser. No. 615,327 Claims priority, application Great Britain, Feb. 24, 1966, 8,166/66; June 13, 1966, 26,275/66; Oct. 14, 1966, 46,072/66 US. Cl. 424-330 2 Claims Int. Cl. A61k 25/00; C08b 25/00 ABSTRACT OF THE DISCLOSURE Pharmaceutical compositions, for example, tablets, containing a diphenylpropQ-enylamine derivative, for example, N,N-dimethyl-3,3-diphenylprop-2-enylamine hydrochloride. Useful as antidepressants.

This invention relates to new pharmaceutical compositions and more particularly it relates to new pharmaceutical compositions having antidepressant activity.

Certain diphenylalkenylamine derivatives are known compounds, but it was not known heretofore that compounds of this type were useful as antidepressants. We have now made the unexpected discovery, and herein lies the basis of this invention, that compounds of this type have antidepressant activity.

According to the invention we provide pharmaceutical compositions comprising at least one alkene derivative of the formula:

C=OH.CHz.NR R B y wherein R and R which may be the same or different, stand for hydrogen atoms or alkyl or aralkyl radicals, and one or both of the phenyl radicals A and B may optionally be substituted with one or two substituents selected from halogen atoms and trifiuoromethyl, alkyl and alkoxy radicals, or a pharmaceutically-acceptable acid-addition salt thereof, and a pharmaceutically-acceptable diluent or carrier.

It is to be understood that the above definition of alkene derivatives includes all stereoisomeric forms thereof, for example the cisand trans-isomers, and mixtures thereof.

As a suitable value for R or R when it stands for an alkyl or aralkyl radical there may be mentioned, for example, an alkyl radical of not more than 6 carbon atoms, and more particularly an alkyl radical of not more than 2 carbon atoms, for example the methyl or ethyl radical, or a phenylalkyl radical of not more than 11 carbon atoms, and more particularly a phenylalkyl radical of not more than 9 carbon atoms, for example the benzyl radical.

The substituent(s) which may optionally be present in one or both of the phenyl radicals A and B may be selected from fluorine, chlorine and bromine atoms, and the trifluoromethyl radical, and alkyl and alkoxy radicals of "ice not more than 6 carbon atoms, and more particularly alkyl and alkoxy radicals of not more than 2 carbon atoms, for example the methyl and methoxy radical.

A preferred group of active ingredients for use in the compositions of the invention consists of alkene derivatives of the above formula wherein R stands for a hydrogen atom or the methyl radical, R stands for the methyl or ethyl radical, and one or both of the phenyl radicals A and B is or are optionally substituted with a halogen atom, and pharmaceutically-acceptable acid-addition salts thereof.

As alkene derivatives which may be used as active ingredients in the pharmaceutical compositions of the invention there my be mentioned, for example,

N,-N-dimethyl-3 ,3-diphenylpr0p-2-enylamine,

N,N-diethyl-3,3-diphenylprop-2-enylamine,

N,N-dimethyl-3- (4-chlorophenyl -3-phenylprop-2- enylamine,

N,N-dimethyl-3- (4-fluorophenyl -3-phenylprop-2- enylamine,

3 ,3-diphenylprop-2-enylamine,

N-ethyl-3,3-diphenylprop 2-enylamine,

N-n-butyl-3,3-diphenylprop-Z-enylamine,

N,N-diethyl3,3-di- (4-methylphenyl prOp-Z-enylamine,

3- 4-methoxyphenyl -3 -phenylprop2-eny1amine,

N-methyl-3 ,3-diphenylprop-Z-enylamine,

N,N-dimethyl-3- (3-fluorophenyl -3-phenylprop-2- enylamine,

N,N-dimethyl-3-phenyl-3- (2-totyl prop-Z-enylamine,

N,N-dimethyl-3 (Z-methoxyphenyl -3-phenylprop-2- enylamine,

N,N-dimethyl-3,3-bis- (4-chlorophenyl) prop-2- enylamine,

N,N-dimethyl-3,3-bis- 3-fluorophenyl prop-2- enylamine,

N,N-dimethyl-3 ,3-bis- (4-fluoropheny1) prop-2- enylamine,

N,N-dimethyl-3- (4-chlorophenyl -3- (4-fluorophenyl) prop-2-enylamine,

N,N-dimethyl-3- (4-chlorophenyl) -3- Z-methoxyphenyl) prop-Z-enylamine,

N,N-dimethyl-3- (4-chlorophenyl) -3- (3-fluorophenyl) prop-Z-enylamine,

N,N-dirnethy1-3 -phenyl-3 (3 -trifluoromethylphenyl) prop-Z-enylamine,

N,N-dimethyl-3 ,3-bis- 3-trifluoromethylphenyl prop- 2-enylamine,

N,N-dimethyl-3 (4-bromophenyl -3 -phenylprop-2- enylamine,

N-methyl- 3- 4-fiuorophenyl) -3 -phenylprop-2- enylamine,

N-methyl-3 ,3-bis- (4-fluorophenyl) prop-2-enylamine,

N-methyl-3- (4-chlorophenyl) -3-phenylprop-2- enylamine,

N-methyl-3 3-bis- 3-fluorophenyl prop-2-enylamine,

N-methyl-3,3-bis- (4-chlorophenyl prop-Z-enylamine,

N-methyl-3-phenyl-3-(2-toly1)prop-2-enylamine,

N-benzyl-N-methyl-3,3-bis- (4-fiuorophenyl prop-2- enylamine and N-benzyl-N-methyl-3,3-bis- (4-fluorophenyl prop-2- enylamine, and

pharmaceutically-acceptable acid-addition salts thereof.

Preferred compounds are N,N-dimethyl-3,3-diphenylprop- 2-enylamine and pharmaceutically-acceptable acid-addition salts thereof, for example the hydrochloride.

As suitable acid-addition salts there may be mentioned salts derived from inorganic or organic acids affording pharmaceutically-acceptable anions, for example hydrochlorides. oxalates, citrates, maleates or tartrates.

Suitable pharmaceutically-acceptable diluents or carriers for use as excipients in the compositions of the invention are those known to the art and used in the preparation of pharamecutical formulations for human and veterinary medication.

The pharmaceutical compositions of the invention include compositions which are suitable for oral administration. These include, for example, solid compositions, for example tablets, pills, capsules, dispersible powders and granules, which may optionally be coated, for example, with a sweetening agent and/or a protective material designed to modify the distribution and absorption of the active ingredient or ingredients in the digestive tract. They also include orally-administrable semi-solid or liquid formulations, for example pharmaceutically-acceptable emulsions, syrups, dispersions and solutions, either for administering per se with or Without flavouring agents or after confinement in some suitable way, for example in capsules.

The pharmaceutical compositions of the invention also include liquid compositions which are sterile aqueous solutions, suspensions or emulsions, or sterile non-aqueous solutions or suspensions which can be administered by injection, for example intravenously, subcutaneously or intramuscularly. Those injectable compositions of the invention which are suspensions contain their particulate matter in a finely divided form, for example in a micropulverised form, and those compositions which are aqueous suspensions may optionally contain small amounts of such agents as are commonly used to facilitate the manufacture and maintain the efiicacy of aqueous suspensions, for example dispersing agents and suspending agents.

Suitable vehicles for the non-aqueous solutions and suspensions of the invention include, for example, watermiscible non-toxic vehicles, for example propylene glycol and polyethylene glycol, and water-immiscible non-toxic vehicles, for example injectable vegetable oils, for example arachis oil, and oil-like injectable organic esters, for example dibutyl succinate. The said water-immiscible vehicles may also contain metallic soaps, for example aluminium stearate.

The sterile injectable solutions, suspensions or emulsions of the invention may be obtained sterile by known procedures, for example by aseptic formulation, by Seitz filtration, by irradiation, by the incorporation of sterilising agents in the compositions, or by heat treatment.

The compositions of the invention include pharmaceutical compositions which are sterile powders comprising the active ingredient or ingredients together with such non-toxic pharmaceutical excipients as are required to provide, on mixing with water, sterile aqueous solutions or suspensions suitable for parenteral administration.

The alkene derivatives which are used as the active ingredients in the pharmaceutical compositions of this invention may be obtained by the dehydration of a propanolamine derivative of the formula:

CHLNRXR2 C7 wherein A, B, R and R have the meanings stated above, or an acid-addition salt thereof, by conventional procedures.

The invention is illustrated but not limited by the following examples in which the parts are by weight:

Example 1 A mixture of 25 parts of N,N-dimethyl-3,S-diphenylprop-2-enylamine hydrochloride, 125 parts of maize starch, 270 parts of calcium phosphate and 1 part of magnesium stearate is compressed, and the compressed material is then broken down into granules by passage through a 16-mesh screen. The granules so obtained are then compressed into tablets which are suitable for oral administration for therapeutic purposes.

The process described above is repeated except that the N,N-dimethyl-phenylprop-Z-enylamine hydrochloride is replaced by a pharmaceutically-acceptable acid-addition salt of one of the following compounds:

N,N-diethyl-3,3 -diphenylprop-Z-enylamine,

N,N-dimethyl-3- (4-chlorophenyl) -3-phenylprop-2-enylamine,

N,N-dimethyl-3- (4-fiuorophenyl 3-phenylprop-2-enylamine,

3 ,3-diphenylprop-Z-enylamine,

N-ethyl-3 ,3-diphenylprop-2-enylamine,

N,N-di-n-propyl-3,3-diphenylprop-2-enylamine,

N,N-di-n-butyl-3 ,3-diphenylprop-2enylamine,

N-n-butyl-3 3-diphenylprop-2-enylamine,

N,N-diethyl-3 ,3 -di- (4-methylphenyl prop-2-enylamine,

3- (4-methoxyphenyl -3 -phenylprop-2-enylamine,

N- 3,3-diphenylprop-2-enyl piperidine and N- 3,3 -diphenylprop-2-enyl morpholine.

In a similar manner there are obtained tablets which are suitable for oral administration for therapeutic purposes.

Example 2 A mixture of 25 parts of N-methyl-3,3-diphenylprop-2- enylamine hydrochloride, 125 parts of maize starch, 270 parts of calcium phosphate and 1 part of magnesium stearate is compressed, and the compressed material is then broken down into granules by passage through a l6-mesh screen. The granules so obtained are then compressed into tablets which are suitable for oral administration for therapeutic purposes.

N-methyl-3,3-diphenylprop-Z-enylamine hydrochlorid may be obtained as follows:

A mixture of 9 parts of N-methyl-3,3-diphenyl-3-hydroxypropylamine, parts of acetic acid, and 30 parts of 10 N-hydrochloric acid is heated at C. for 2 hours. The solvent is then evaporated in vacuo, the residue is made strongly alkaline with 2 N-sodium hydroxide solution, and is then extracted with 250 parts of ether. The ethereal extract is washed with water and then dried with anhydrous calcium sulphate. The ether is evaporated from the solution, and an ethereal solution of hydrogen chloride is added to the residual oil. The mixture is filtered and the solid residue is crystallised from n-butyl acetate. There is thus obtained N-rnethyl-3,3-diphenylprop-2-enylamine hydrochloride, M.P. 146l48 C.

N-methyl-3,3-diphenyl-3 hydroxypropylamine (M.P. l48-150 C., crystallised from n-butyl acetate) may be obtained in conventional manner by the interaction of phenyl magnesium bromide and w-methylaminopropiophenone.

Example 3 A mixture of 25 parts of N,N-dimethyl-3-(3-fluorophenyl)-3-phenylprop-2-enylamine hydrochloride, parts of maize starch, 270 parts of calcium phosphate and 1 part of magnesium stearate is compressed, and the compressed material is then broken down into granules by passage through a 16-mesh screen. The granules so obtained are then compressed into tablets which are suitable for oral administration for therapeutic purposes.

The process described above is repeated except that the N,N-dimethyl-3-(3-fluorophenyl) 3 phenylprop-2-eny1- amine hydrochloride is replaced by any one of the following compounds:

(3:011.CHLNR IR Salt, M.P. C.)

A B R R crystallisation solvent Ph 2-MePh. Me Me (a)194 butyl acetate Ph 2-MeO-Ph Me.. Me.. (a) 166 butyl acetate 4ClPh 4-Ol-Ph Me. Me. (a) 232 acetone. 3-F-Ph 3-F-Ph Me Me.. (a)156 benzene. 4FPh 4-FPh Me Me (a) 212 ethyl acetate. 4-OlPh 4-FPh Me Me (a)196 ethyl acetate. 4 C1-Ph 2-MeOPh Me Me (a) 159 butyl acetate. 4-ClPh 3-F-P (a) 144butano1.

- (a) 180 ethyl acetate. (a) 144 ethyl acetate.

(a) hydrochloride, (b) oxalate.

In a similar manner there are obtained tablets which are suitable for oral administration for therapeutic purposes.

N,N-dimethyl-3-(3-fluorophenyl) 3 phenylprop-Z- enylamine hydrochloride may be obtained as follows:

A mixture of 9 parts of N,N-dimethyl-3-(3-fiuorophenyl)-3-phenyl-3-hydroxypropylamine, 150 parts of acetic acid and 40 parts of 10 N-hydrochloric acid is heated at 95 C. for 2 hours, and is then kept at C. for 12 hours. The solvent is then evaporated and the residue is made strongly alkaline with aqueous sodium hydroxide and is then extracted with 200 parts of ether. The ethereal extract is washed with water and dried over anhydrous calcium sulphate, and the ether is then removed from the extract by evaporation. An ethereal solution of hydrogen chloride is added to the residue, and the precipitated solid is collected by filtration and is crystallised from butyl acetate. There is thus obtained N,N-dimethyl-3-(3-fluorophenyl)-3-phenylprop-2-enylamine hydrochloride, M.P. 148 C.

The hydroxypropane derivative used as starting material may be obtained in conventional manner by the interaction of the appropriate Grignard reagent with the appropriate ketone.

The other diphenylalkenylamine derivatives listed above may be obtained in similar manner to that described for N,N-dimethyl-3-(3-fluorophenyl) 3 phenylprop-Z-enylamine hydrochloride.

The alkene derivatives which are used as active ingredients in the pharmaceutical compositions of this invention are active in a procedure that is standard in the art for testing for antidepressant agents. These results were obtained in standard experimental animals (mice), and they presumptively indicate utility in man. On the basis of these results obtained in standard experimental animals and data obtained in related laboratory studies, it is considered reasonable to expect that pharmaceutical compositions of this invention could be used clinically in man. The total daily oral dose is expected to be in the range 30 to 300 mg. per kg. man, administered, for example, in the form of a tablet or capsule.

What Iclaim is:

1. A method for effecting an antidepressant action in a host in need of such action which comprises administering to said host an effective amount of an alkene derivative selected from the group consisting of a compound of the formula:

wherein R is selected from the group consisting of hydrogen, methyl and ethyl, R is selected from the group consisting of hydrogen, methyl, ethyl and benzyl, A is selected from the group consisting of phenyl, hal-ogenophenyl, trifiuoromethylphenyl and tolyl, and B is selected from the group consisting of phenyl, halogenophenyl, trifluoromethylphenyl, tolyl and anisyl, and pharmaceuticallyacceptable acid-addition salts thereof.

2. A method for effecting an antidepressant action according to claim 1 which comprises administering to said host an effective amount of N,N-di1nethyl-3,3-diphenylprop-2-enylamine or a pharmaceutica-lly-acceptable acid-addition salt thereof.

References Cited FOREIGN PATENTS 525,752 6/1956 Canada. 1,122,514 1/ 1962 Germany. 1,149,002 5/ 1963 Germany. 1,203,247 10/ 1965 Germany.

ALBERT T. MEYERS, Primary Examiner.

S. I. FRIEDMAN, Assistant Examiner.

U.S. Cl. X.R. 424--325 

